Thiazole compound

ABSTRACT

The invention relates to pharmaceutical compositions for use in treating ulcers or hypersecretion in mammals comprising a compound of formula Ia ##STR1## where Hal is a halogen atom, R 1  is hydrogen or alkyl of 1-6 carbon atoms, R is hydrogen, alkyl of 1-5 carbon atoms (which may be substituted by two or more chlorine or bromine atoms), alkenyl of 2 to 5 carbon atoms, perfluoroalkyl of 1-5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, R 3  is hydrogen, alkyl of 1-6 carbon atoms, or COR 4  where R 4  is as defined for R and R and R 4  may be the same or different, and a pharmaceutically acceptable carrier. 
     Methods of treatment of affected mammals and some novel compounds are also described.

This is a division, of application Ser. No. 799,911, filed May 23, 1977now 4,148,904.

This invention relates to novel pharmaceutical compositions withanti-ulcer or anti-secretory activity and methods of treating ulcers orhypersecretion in mammals. Application Ser. No. 799,911 is acontinuation-in-part of my copending application Ser. No. 740,633 filedNovember 10, 1976 now abandoned.

Johnson and Nasutavicus (J. Org. Chem. 1963, 28, 1877-83), havedescribed a new synthesis of 2-bromo-4-amino-thiazoles. In U.S. Pat. No.3,244,723 the same authors have described thiazoles, including2-bromo-4-aminothiazoles, with various biological activities namelyagainst fungus, brown root, bean aphid, two spotted spider mite, plumcurculio, northern fat-headed mannow and waterplantcoontail.

Some related thiazoles are described in U.S. Pat. No. 3,850,945(Edwards). This patent is concerned with 2-hydroxyalkoxythiazoles, which2- substituent is also further substituted, the compounds being said tobe useful as cardiovascular agents. In this patent certain 2-halothiazoles are described as intermediates including2-bromo-4-acetamidothiazole (preparation 12) and2-chloro-4-formylamino-thiazole (preparation 22).

No pharmaceutical applications of any of these 2-halothiazoles have beenreported so far as I am aware. I have now surprisingly found that some2-bromo-4-acylamino-thiazoles and 2-bromo-4-diacylaminothiazoles fallingwithin the class of compounds disclosed in these publications haveanti-ulcer or anti-secretory activity whereas other closely relatedcompounds are inactive. I have also found that some related2-chloro-thiazoles have anti-ulcer or anti-secretory activity.

Anti-ulcer activity was determined by the stress-induced erosion test ofSenay & Levine, Proc. Soc. Exp. Biol. Med. 124, 1221-3(1967) andanti-secretory activity by the test of H. Shay, D. Sun and H.Greenstein, Gastroenterology, 1954, 26, 903-13. The compounds whichpossess one or both these activities are considered to be anti-ulceragents which can be used for the treatment of ulcers or hypersecretionin mammals.

The present invention provides a pharmaceutical composition comprising acompound of formula Ia ##STR2## where Hal is a halogen atom, R¹ ishydrogen or alkyl of 1-6 carbon atoms, R is hydrogen alkyl of 1-5 carbonatoms (which may be substituted by one or more of the following:trifluoromethyl, methoxy, ethoxy, amino, loweralkylamino,diloweralkylamino, hydroxy, or cyano or by two or more chlorine orbromine atoms), alkenyl of 2 to 5 carbon atoms, alkynyl of 2 to 5 carbonatoms, perfluoroalkyl of 1-5 carbon atoms, cycloalkyl of 3 to 5 carbonatoms, R³ is hydrogen, alkyl of 1-6 carbon atoms, or COR⁴ where R⁴ is asdefined for R and R and R⁴ may be the same or different, and apharmaceutically acceptable carrier.

In the compounds of formula Ia, Examples of R are for the alkyl groupmethyl, ethyl, n-propyl, isopropyl or n-butyl; for alkenyl group vinyl,prop-1-enyl, but-1-enyl, but-2-enyl; for the alkynyl group ethynyl,prop- 2-ynyl, but-2-ynyl; for the cyclo alkyl group cyclopropyl,cyclobutyl and cyclopentyl, for the perfluoroalkyl group,trifluoromethyl and pentafluoroethyl. R³ may be any of the alkyl groupsdisclosed for R but is preferably methyl.

When the term "lower alkyl" is used in this specification either aloneor as part of another radical it means an alkyl group of 1 to 6 carbonatoms which may have a straight or branched chain e.g. methyl, ethyl,n-propyl, iso-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, or n-hexyl.Preferred examples of loweralkylamino are methylamino and ethylamino.Examples of diloweralkyl amino are dimethylamino and diethylamino.

In a preferred aspect the invention provides a pharmaceuticalcomposition for use in the treatment of ulcers or hypersecretioncomprising a compound of formula Ia ##STR3## where Hal is a halogenatom, R¹ is hydrogen or alkyl of 1-6 carbon atoms, R is hydrogen, oralkyl of 1-5 carbon atoms (which may be substituted by two or morechlorine or bromine atoms), alkenyl of 2 to 5 carbon atoms,perfluoroalkyl of 1-5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms,R³ is hydrogen, alkyl of 1-6 carbon atoms, or COR⁴ where R⁴ is asdefined for R and R and R⁴ may be the same or different, and apharmaceutically acceptable carrier.

R¹ when alkyl of 1-6 carbon atoms may be any of the lower alkyl radicalsdiscussed above but is preferably methyl or ethyl. Hal may be chlorine,bromine, fluorine or iodine but preferably is chlorine or bromine.

Preferably the pharmaceutical composition is in unit dosage form e.g. astablets or capsules.

Many of the compounds of formula I either fall within the genericdisclosure or are specifically disclosed in the publications of Johnsonand Nasutavicus or Edwards mentioned above.

The pharmaceutical compositions of this invention are distinguished fromknown insecticidal or anti-fungal compositions or chemical intermediatessince these are not formulated to pharmaceutical standards, nor are theyin unit dosage forms.

For the pharmaceutical carrier any suitable carrier known in the art canbe used to prepare the pharmaceutical compositions. In such acomposition, the carrier may be a solid, liquid, or mixture of a solidand a liquid. Solid form compositions include powders, tablets andcapsules. A solid carrier can be one or more substances which may alsoact as flavouring agents, lubricants, solubilisers, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material. In powders the carrier is a finely divided solidwhich is in admixture with the finely divided active ingredient. Intablets the active ingredient is mixed with a carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired. The powders and tablets preferably containfrom 995 to 99 , preferably 10-80% of the active ingredient. Suitablesolid carriers are magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low melting wax and cocoa butter. Theterm "composition" is intended to include the formulation of an activeingredient with encapsulating material as carrier to give a capsule inwhich the active ingredient (with or without other carriers) issurrounded by carrier, which is thus in association with it. Similarlycachets are included.

Sterile liquid form compositions include sterile solutions, suspensions,emulsions, syrups and elixirs. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable carrier, such as sterilewater, sterile organic solvent or a mixture of both. The activeingredient can often be dissolved in a suitable organic solvent, forinstance aqueous propylene glycol containing from 10 to 75% of theglycol by weight is generally suitable. In other instances compositionscan be made by dispersing the finely-divided active ingredient inaqueous starch or sodium carboxymethyl cellulose solution, or in asuitable oil, for instance arachis oil.

Preferably the pharmaceutical composition is in unit dosage form, thecomposition is sub-divided in unit doses containing appropriatequantities of the active ingredient; the unit dosage form can be apackaged composition, the package containing specific quantities ofcompositions, for example packeted powders or vials or ampoules. Theunit dosage form can be a capsule, cachet or tablet itself, or it can bethe appropriate number of any of these in packaged form. The quantity ofactive ingredient in a unit dose of composition may be varied oradjusted from 10 to 500 mg or more e.g. 25 mg to 250 mg, according tothe particular need and the activity of the active ingredient. Theinvention also includes the compounds in the absence of carrier wherethe compounds are in unit dosage form.

The anti-ulcer compositions of the invention will be administered orallyin either liquid or solid composition form. These compositions mayinclude one or more antacid ingredients e.g. aluminum hydroxide,magnesium hydroxide or bismuth carbonate, aluminium glycinate, calciumcarbonate, magnesium trisilicate, sodium bicarbonate or the alumina geldescribed in British Specification No. 1,284,394.

The preferred compounds of formula Ia used in the pharmaceuticalcompositions of the invention are those in which Hal is chlorine orbromine, R³ is hydrogen or methyl and R is hydrogen or alkyl of 1-3carbon atoms preferably methyl. Preferably R¹ is hydrogen or methyl.Particularly preferred compounds are 4-acetamido-2-bromothiazole,4-acetamido-2-bromo-5-methylthiazole, 4-acetamido-2-chlorothiazole,2-chloro-4-formamido-thiazole, and2-bromo-4-(N-methylacetamido)thiazole.

Another preferred group of compounds used in the pharmaceuticalcompositions of the invention are those of formula Ia when R³ is COR⁴and R⁴ is hydrogen or alkyl of 1-5 carbon atoms. In these compoundpreferably R and R⁴ are both methyl or one of R and R⁴ is hydrogen andthe other is methyl. Compounds of this group where Hal is chlorine orbromine, R¹ is hydrogen, and R and R⁴ are selected from hydrogen andmethyl have very good antisecretory activity, e.g. 4-(N-acetyl-N-formyl)amino-2-bromothiazole and 4-diacetylamino-2-bromothiazole.

The compounds of formula Ia wherein R³ is hydrogen or alkyl of 1-6carbon atoms may be prepared by known methods e.g. by acylation of thecorresponding 4-amino-thiazoles or 4-N-alkylaminothiazoles of formula II##STR4## where Hal and R¹ are as previously defined and R³ is hydrogenor alkyl of 1-6 carbon atoms.

Standard acylating agents capable of introducing the group RCO may beused e.g. the acid chloride RCOCl, acid anhydride ##STR5## or mixedanhydride ##STR6## where R is as defined above and R² is another Rgroup. Formylation may be carried our using a mixed anhydride of formicand acetic acids. This reagent can be produced from formic acid andacetic anhydride.

When the group R is alkyl carrying a substituent functional group thenone such group may be converted to another by standard methods.

Mono formyl compounds of formula Ia where R is hydrogen and R³ ishydrogen may be prepared by treatment of the azide of formula III##STR7## wherein X and R¹ are as defined in connection with formula Iawith a formylating agent such as the mixed anhydride of formic andacetic acids.

Thus the azides of formula (III) may be prepared by Curtiusrearrangement of a thiazole ester of formula (IV) ##STR8## where R¹ isas defined in connection with formula Ia and R³ is lower alkyl and X ischlorine or bromine.

The ester of formula (IV) is treated with hydrazine to give thehydrazide of formula (V) ##STR9## followed by nitrous acid to give thecarbonyl azide of formula (III)

The starting compounds of formula II wherein Hal is bromine aredescribed in J. Org. Chem., 1963, 28, 1877-83 or may be prepared byanalogous methods. The compounds of formula II where Hal is chlorine maybe prepared by methods described by Erlenmeyer et al Helv. Chim. Acta,29, 1229-31.

Some compounds of formula Ia are known compounds which are described inthe two literature references mentioned above or in U.S. Pat. Nos.3,244,723, or 3,850,945.

Compounds of formula Ia, wherein R³ is COR⁴ and R⁴ is hydrogen or alkylof 1 to 5 carbon atoms e.g. a compound of formula VI ##STR10## whereinHal is a halogen atom, and R¹ and R are as defined in connection withformula I, may be prepared by acylation of a compound of formula Iawhere R³ is hydrogen using an acylating agent containing the group--CORe.g. an acid halide R⁴ CO Hal where Hal is chlorine or bromine or ananhydride or mixed anhydride. In this way compounds of formula III withdifferent acyl radicals on the nitrogen may be prepared.

When a compound of formula Ia is prepared in which R³ is hydrogen thismay be alkylated to give a compound of formula Ia where R³ is alkyl of1-6 carbon atoms. This alkylation can be carried out by treatment withan alkali metal hydride (e.g. sodium hydride) or equivalent base and analkylating agent (such as di(lower alkyl)sulphate, alkyl tosylate or alower alkyl halide).

Pharmacological Test Results

When tested orally in rats 4-acetamido-2-bromothiazole showed moderateactivity at 100 mpk in the test of Senay & Levine mentioned above. Thecompound displayed outstandingly good anti-secretory activity in thetest of Shay et al at 30 and 10 mpk and was also active at 3 mpk.4-Acetamido-2-bromo-5-methylthiazole was inactive at 100 mpk in the testof Senay & Levine but displayed outstandingly good activity in theanti-secretory test of Shay et al at 30 and 10 mpk.

When tested orally in rats 4-diacetylamino-2-bromothiazole had nosignificant activity at 100 mpk in the test of Senay & Levine mentionedabove. The compound displayed outstandingly good anti-secretory activityin the test of Shay et al at 30 and 10 mpk but was inactive at 3 mpk.4-Acetamino-2-chlorothiazole displayed outstandingly good activity inthe anti-secretory test of Shay et al at 10 mpk and also good activityat 30 mpk and 3 mpk.

Detailed test results are shown in Table I.

                                      TABLE 1                                     __________________________________________________________________________              Stress-in-                                                                    duced erosion                                                                 (Senay &                                                                             Anti-secretory                                                          Levine)                                                                             (Shay et al)                                                           mpk    mpk                                                          Compound  p.o.                                                                              Inhib                                                                            ID Vol Conc  Free H.sup.+                                                                        Total H.sup.+                             __________________________________________________________________________    4-acetamido-2-                                                                bromothiazole                                                                           100 54%                                                                              30 -79%                                                                              Insuff. for titration                                            30 40%                                                                              10 -80%                                                                        3 -42%                                                                              -12%  -44%  -40%                                                              NS                                                    4-acetamido-2-                                                                           50 NS 30 75% Insuff. for titration                                 bromo-5-methyl-  10 -57%                                                                              -44%  -68%  -57%                                      thiazole          3 Not significant                                           2-bromo-4-iso-                                                                          100 70%                                                                              30 Not significant                                           butyramidothia-                                                               zole                                                                          2-bromo-4-                                                                              100 50%                                                                              30 -31%                                                                              -8%NS -38%  -35%                                      trifluoroacetamido                                                                          NS                                                              thiazole                                                                      2-bromo-4-prop-                                                                         100 NS 30 -62%                                                                              -35%  -70%  -64%                                      ionamidothiazole  10                                                                              Not significant                                           2-bromo-4-(cyclo-                                                                       100 70%                                                                              30 -67%                                                                              -34%  -75%  -68%                                      propylcarboxamido)                                                                             10 Not significant                                           thiazole                                                                      4-diacetylamino-2-                                                            bromothiazole                                                                           109 29%                                                                              30 -72%                                                                              -22%NS                                                                              -71%  -68%                                                    NS 10 -54%                                                                              -30%  -66%  -57%                                                        3 Not Significant                                           4-acetamido-2-                                                                          100 50%                                                                              30 -54%                                                                              -8%NS -39%NS                                                                              -43%                                      chlorothiazole   10 -79%                                                                              -51%  -84%  -79%                                                        3 -57%                                                                              -56%  -78%  -55%                                      2-bromo-4-n-                                                                            100 29%                                                                              30 -34%                                                                              -20% NS                                                                             -42%  -39%                                      butyramidothia-                                                                             NS    NS                                                        zole                                                                          4-acrylamido 2                                                                          100 31%                                                                              30 -29%      -34%  -32%                                      bromothiazole NS        -8%NS                                                 2-bromo-4-trichloro-                                                                    100 36%                                                                              30 -31%                                                                              -12%  -39%  -35%                                      acetamidothiazole                                                                           NS                                                              __________________________________________________________________________     NS = Not Significant                                                     

When tested orally in rats 2-chloro-4-form midothiazole was inactive at100 mpk in the test of Senay & Levine mentioned above. The compounddisplayed good anti-secretory activity in the test of Shay et al at 30and 10 mpk but was inactive at 3 mpk.4-(N-acetyl-N-formyl)amino-2-bromothiazole showed good activity in thetest of Shay et al at 30 mpk.

                                      Table 2                                     __________________________________________________________________________    Compound Stress-induced erosion                                                                Anti-secretory                                               (Senay & Levine) (Shay et al)                                                           mpk                                                                              %   mpk         Free                                                                              Total                                                  p.o.                                                                             Inhib                                                                             ID  Vol Conc                                                                              H.sup.+                                                                           H.sup.+                                      __________________________________________________________________________    2-chloro-4-form-                                                              amidothiazole                                                                           100                                                                              25  30  -53%                                                                              -38%                                                                              -69%                                                                              -60%                                                          10  -59%                                                                              -16%                                                                              -64%                                                                              -60%                                                                  NS                                                   2-bromo-4-form-                                                                         100                                                                              In- 100 -55%                                                                              Insufficient gastric                                 amidothiazole                                                                              active      juice for titration                                                   30  Inactive                                                 4-(N-acetyl-N-                                                                          100                                                                              In- 30  -63%                                                                              -21%                                                                              -68%                                                                              -59%                                         formyl)amino-2-                                                                            active                                                           bromothiazole                                                                 __________________________________________________________________________     NS = not significant                                                     

When tested orally in rats 2-bromo-4-(N-methylacetamido)thiazoledisplayed good activity in the test of Shay et al at 30 mpk but weakactivity at 10 mpk. It was inactive in the test of Senay & Levine at 30and 100 mpk.

                                      Table 3                                     __________________________________________________________________________               Anti-secretory                                                                (Shay et al)                                                                  mpk            Free                                                                              Total                                           Compound   i.d.                                                                             Vol   Conc  H.sup.+                                                                           H.sup.+                                         __________________________________________________________________________    2-bromo-4-N-methyl-                                                                      -30                                                                              -49%  -4% NS                                                                              -53%                                                                              -37%                                            acetamidothiazole                                                                        -10                                                                              -30% NS                                                                             -15% NS                                                                             -38%                                                                              -31% NS                                         __________________________________________________________________________     NS = Not signficant                                                      

The following closely related compounds were inactive in the above tests4-amino-2-bromothiazole hydrobromide [Senay & Levine (100 mpk) Shay (30mpk)], 4-amino-2-bromo 5-methylthiazole hydrobromide [Senay & Levine(100 mpk), Shay (30 mpk)], 4-benzamido-2-bromothiazole [Senay & Levine(100 mpk), Shay (30 mpk)], 4-acetamido-2-bromo-5-phenyl-thiazole [Senay& Levine (100 mpk) Shay (30 mpk)].

The invention includes a method of treating ulcers or hypersection in anafflicted mammal which method comprises administering to said mammal aneffective amount of a compound of formula Ia as defined above.

The amount of compound used will depend on the activity of the compoundand the needs of the mammal being treated. Doses may range from 3 to 100mg/kg.

In the pharmaceutical compositions unit doses may vary from 25 to 500mg. according to the activity of the selected ingredient, preferably 50to 250 mg. per unit dose.

Preferably the compound used is 4-acetamido-2-bromothiazole,4-acetamido-2-bromo-5-methylthiazole, 4-acetamido-2-chlorothiazole,4-diacetamido-2-bromothiazole, 2-chloro-4-formamidothiazole or4-(N-acetyl-N-formyl)amino-2-bromothiazole.

The following examples illustrate pharmaceutical compositions inaccordance with the invention.

EXAMPLE A

    ______________________________________                                        Suspension             % w/v                                                  ______________________________________                                        Aluminium hydroxide gel B.P. 5% Al.sub.2 O.sub.3                                                     80% = 4% Al.sub.2 O.sub.3                              Magnesia Magma 12%, w/v MgO                                                                          10%                                                    4-acetamido-2-bromothiazole                                                                          2.0%                                                   Glycerin B.P.          3.0%                                                   Alcohol 60 O.P.*       0.08%                                                  Peppermint oil B.P.    0.015%                                                 Saccharin sodium B.P.  0.01%                                                  Methyl p-hydroxybenzoate sodium salt                                                                 0.1%                                                   Propyl p-hydroxybenzoate sodium salt                                                                 0.02%                                                  Butyl p-hydroxybenzoate sodium salt                                                                  0.01%                                                  Water q.s. ad          100.00%                                                ______________________________________                                         *O.P. denotes overproof, 60 O.P. represents 91% w/v Ethanol/Water        

The above suspension is prepared by the following procedure. Add to theAlumina gel Magnesia Magma followed by the thiazole dispersed inglycerin, the peppermint oil dissolved in alcohol, the saccharin sodiumdissolved in water, and the p-hydroxybenzoates dissolved in water. Makeup to volume of water and stir well. Dose 5 ml. t.d.s.

EXAMPLE B Antacid Tablet (chewable)

    ______________________________________                                        Saccharin              1.0 mg.                                                Hydrated alumina sucrose powder                                                                      750.0 mg.                                              4-acetamido-2-bromothiazole                                                                          100.0 mg.                                              Mannitol B.P.          170.0 mg.                                              Maize starch B.P. dried                                                                              30.0 mg.                                               Talc. purified B.P.    28.0 mg.                                               Magnesium stearate B.P.                                                                              20.0 mg.                                               Peppermint oil B.P.    1.0 mg.                                                                       1100.0 mg.                                             ______________________________________                                    

Antacid tablets of the above formulation are prepared by the followingprocedure.

Triturate peppermint oil with talc (screen 40 mesh). Add the triturate,and other ingredients to a blender and mix thoroughly.

Slug the powder to large hard slugs.

Granulate the slugs through a 14 mesh screen.

Compress the granules on a suitable compression machine to give tabletsof the required size.

EXAMPLE C Anti-ulcer tablet (without antacid)

    ______________________________________                                                             mg/tablet                                                ______________________________________                                        4-acetamido-2-bromothiazole                                                                          100 mg.                                                Celutab                147.5 mg.                                              Mag. Stearate          2.5 mg.                                                                       250.0 mg.                                              ______________________________________                                    

The tablets are prepared by the following method.

Blend the ingredients in a suitable blender. Compress the blendedingredients on a suitable compression machine to form tablets of theabove composition.

Celutab is a commercial product comprising 90-2% dextrose. 3-5% maltoseremainder higher glucose saccharides. Spray crystallised.

EXAMPLE D

A suspension is prepared as described in Example A but replacing4-acetamido-2-bromothiazole by 4-acetamido-2-bromo-5-methylthiazole.

EXAMPLE E

An antacid tablet is prepared as described in Example B but replacing4-acetamido-2-bromothiazole by 4-acetamido-2-bromo-5-methylthiazole.

EXAMPLE F

An anti-ulcer tablet is prepared as described in Example C but replacing4-acetamido-2-bromothiazole by 4-acetamido-2-bromo-5-methylthiazole.

EXAMPLE G

    ______________________________________                                        Suspension             % w/v                                                  ______________________________________                                        Aluminium hydroxide gel B.P. 5% Al.sub.2 O.sub.3                                                     80% = 4% Al.sub.2 O.sub.3                              Magnesia Magma 12% w/v MgO                                                                           10%                                                    4-diacetylamino-2-bromothiazole                                                                      2.0%                                                   Glycerin B.P.          3.0%                                                   Alcohol 60 O.P.*       0.08%                                                  Peppermint oil B.P.    0.015%                                                 Saccharin sodium B.P.  0.01%                                                  Methyl p-hydroxybenzoate sodium salt                                                                 0.1%                                                   Propyl p-hydroxybenzoate sodium salt                                                                 0.02%                                                  Butyl p-hydroxybenzoate sodium salt                                                                  0.01%                                                  Water q.s. ad          100.00%                                                ______________________________________                                         *O.P. denotes overproof. 60 O.P. represents 91% w/v Ethanol/Water.       

The above suspension is prepared by the following procedure. Add to theAlumina gel, Magnesia Magma followed by the thiazole dispersed inglycerin, the peppermint oil dissolved in alcohol, the saccharin sodiumdissolved in water, and the p-hydroxybenzoates dissolved in water. Makeup to volume of water and stir well. Dose: 5 ml. t.d.s.

EXAMPLE H Antacid Tablet (chewable)

    ______________________________________                                        Saccharine             1.0 mg.                                                Hydrated alumina sucrose powder                                                                      750.0 mg.                                              4-diacetylamino-2-bromothiazole                                                                      100.0 mg.                                              Mannitol B.P.          170.0 mg.                                              Maize starch B.P. dried                                                                              30.0 mg.                                               Talc. purified B.P.    28.0 mg.                                               Magnesium stearate B.P.                                                                              20.0 mg.                                               Peppermint oil B.P.    1.0 mg.                                                                       1100.0 mg.                                             ______________________________________                                    

Antacid tablets of the above formulation are prepared by the followingprocedure.

Triturate peppermint oil with talc (screen 40 mesh). Add the triturate,and other ingredients to a blender and mix thoroughly.

Slug the powder to large hard slugs.

Granulate the slugs through a 14 mesh screen.

Compress the granules on a suitable compression machine to give tabletsof the required size.

EXAMPLE I Anti-ulcer tablet (without antacid)

    ______________________________________                                                             mg/tablet                                                ______________________________________                                        4-acetamido-2-chlorothiazole                                                                         100 mg.                                                Celutab                147.5 mg.                                              Mag. Stearate          2.5 mg.                                                                       250.0 mg.                                              ______________________________________                                    

The tablets are prepared by the following method.

Blend the ingredients in a suitable blender. Compress the blendedingredients on a suitable compression machine to form tablets of theabove composition.

Celutab is a commercial product comprising 90-2% dextrose. 3-5% maltoseremainder higher glucose saccharides. Spray crystallised.

EXAMPLE J

A suspension is prepared as described in Example G but replacing4-diacetylamino-2-bromothiazole by 4-acetamido-2-chlorothiazole.

EXAMPLE K

    ______________________________________                                        Suspension             % w/v                                                  ______________________________________                                        Aluminium hydroxide gel B.P. 5% Al.sub.2 O.sub.3                                                     80% = 4% Al.sub.2 O.sub.3                              Magnesia Magma 12% w/v MgO                                                                           10%                                                    2-chloro-4-formamidothiazole                                                                         2.0%                                                   Glycerin B.P.          3.0%                                                   Alcohol 60 O.P.*       0.08%                                                  Peppermint oil B.P.    0.015%                                                 Saccharin sodium B.P.  0.01%                                                  Methyl p-hydroxybenzoate sodium salt                                                                 0.1%                                                   Propyl p-hydroxybenzoate salt                                                                        0.02%                                                  Butyl p-hydroxybenzoate sodium salt                                                                  0.01%                                                  Water q.s. ad          100.00%                                                ______________________________________                                         *O.P. denotes overproof, 60 O.P. represents 91% w/v Ethanol/Water.       

The above suspension is prepared by the following procedure. Add to theAlumina gel Magnesia Magma followed by the thiazole dispersed inglycerin, the peppermint oil dissolved in alcohol, the saccharin sodiumdissolved in water, and the p-hydroxybenzoates dissolved in water. Makeup to volume of water and stir well. Dose 5 ml. t.d.s.

EXAMPLE L Antacid Tablet (chewable)

    ______________________________________                                        Saccharin              1.0 mg.                                                Hydrated alumina sucrose powder                                                                      750.0 mg.                                              2-chloro-4-formamidothiazole                                                                         100.0 mg.                                              Mannitol B.P.          170.0 mg.                                              Maize starch B.P. dried                                                                              30.0 mg.                                               Talc, purified B.P.    28.0 mg.                                               Magnesium stearate B.P.                                                                              20.0 mg.                                               Peppermint oil B.P.    1.0 mg.                                                                       1100.0 mg.                                             ______________________________________                                    

Antacid tablets of the above formulation are prepared by the followingprocedure.

Triturate peppermint oil with talc (screen 40 mesh). Add the triturate,and other ingredients to a blender and mix thoroughly.

Slug the powder to large hard slugs.

Granulate the slugs through a 14 mesh screen.

Compress the granules on a suitable compression machine to give tabletsof the required size.

EXAMPLE M Anti-ulcer tablet (without antacid)

    ______________________________________                                                             mg/tablet                                                ______________________________________                                        2-chloro-4-formamidothiazole                                                                         100 mg.                                                Celutab                147.5 mg.                                              Mag. Stearate          2.5 mg.                                                                       250.0 mg.                                              ______________________________________                                    

The tablets are prepared by the following method.

Blend the ingredients in a suitable blender. Compress the blendedingredients on a suitable compression machine to form tablets of theabove composition.

Celutab is a commercial product comprising 90-2% dextrose. 3-5% maltoseremainder higher glucose saccharides. Spray crystallised.

EXAMPLE O

Compositions are prepared as described in Examples K, L or M byreplacing 2-chloro-4-formamidothiazole with4-(N-acetyl-N-formyl)amino-2-bromothiazole.

EXAMPLE P

Compositions are prepared as described in Examples K, L or M byreplacing 2-chloro-4-formamidothiazole with2-bromo-4(N-methylacetamido)thiazole.

PREPARATION OF THE ACTIVE INGREDIENTS EXAMPLE 14-Acetamido-2-bromothiazole

4-Amino-2-bromothiazole hydrobromide (52 g, 0.2 m) was suspended inacetic anhydride (200 ml) then treated dropwise with pyridine (100 ml),maintaining the temperature at 0° C. by means of an ice bath. After theaddition was complete, the reaction mixture was stirred for 2 h. at roomtemperature then poured onto 20% aqueous sodium acetate (2 l.). Thesolution was cooled, filtered and the precipitate washed with water(2×200 ml.). The product was air dried and recrystallised from acetoneto give the title compound (35 g, 80%) m.p. 165° C.

Found: C, 27.5; H, 2.5; N, 12.7. C₅ H₅ BrN₂ OS requires C, 27.2; H, 2.3;N, 12.7%.

EXAMPLE 2 2-Bromo-4-isobutyramidothiazole

A solution of isobutyryl chloride (4.15 ml., 40 mM) in pyridine (50 ml.)was cooled to 0° C. and treated portionwise with 4-amino-2-bromothiazolehydrobromide (7.8 g, 30 mM). After stirring for 1 h. the reactionmixture was poured onto 20% aqueous sodium acetate solution (500 ml) andextracted with chloroform (3×200 ml.). The combined organic layers weredried and the solvents removed under reduced pressure to yield an oilwhich eventually crystallised. Recrystallisation from 60°-80° petroleumether gave the title compound (2 g, 20%). mp: 95° (Found: C, 34.1; H,3.8; N, 11.3. C₇ H₉ BrN₂ OS requires C, 33.7; H, 3.6; N, 11.2%).

EXAMPLE 3 4-Acetamido-2-bromo-5-methylthiazole

A suspension of 4-amino-2-bromo-5-methylthiazole hydrobromide (50 mM13.7 g) in acetic anhydride (100 ml.) was treated dropwise with pyridine(10 ml.) while cooling in an ice bath. After stirring for 1 hr. thereaction mixture was poured onto 20% aqueous sodium acetate (1l.) andthe aqueous solution extracted with dichloromethane (3×500 ml.). Thecombined organic layers were dried and evaporated under reduced pressureto give an oil which crystallised on trituration with ether. The crudeproduct was recrystallized from ethanol to give the title compound (11.7g, 50%). mp 129° (Found: C, 31.15; H, 3.15; N, 12.3. C₆ H₇ BrN₂ OSrequires: C, 30.6; H, 3.0; N, 11.9%).

EXAMPLE 4 2-Bromo-4-trifluoroacetamidothiazole

4-Amino-2-bromothiazole hydrobromide (19.5 g, 75 mM) was suspended intrifluoroacetic anhydride (200 ml.) and dichloromethane (200 ml.). Themixture was cooled to 0° C. and treated dropwise with pyridine (50 ml.).After the addition was complete the mixture was stirred for 1 hour atroom temperature, then poured onto a mixture of ice cold 20% aqueoussodium acetate solution (1l.) and dichloromethane (500 ml.). The layerswere separated and the aqueous layer extracted with dichloromethane (500ml.). The combined organic layers were dried (MgSO₄) and the solventremoved under reduced pressure. Distillation of the residue gave thetitle compound (18 g, 87%) b.p. 90°-95° C. at 0.3 mm as an oil whichsubsequently solidified. Sublimation (50°-60° C. at 0.01 mm) gaveanalytically pure material mp. 71° C. (Found: C, 22.1; H, 0.8; N, 10.2.C₅ H₂ ON₂ BrF₃ S requires: C, 21.8; H, 0.7; N, 10.2%).

EXAMPLE 5 2-Bromo-4-propionamidothiazole

4-Amino-2-bromothiazole hydrobromide (6.5g.) was suspended in propionicanhydride (25 ml.) with stirring; then treated with pyridine (12.5 ml.)over 15 minutes, maintaining reaction temperature at 0° C. with an icebath. After the addition was complete, the reaction mixture was stirredfor 2 hours at room temperature, then poured onto 20% aqueous sodiumacetate (250 ml.) and stirred for 30 minutes. The precipitate wasremoved by filtration and washed with water. The solid was air dried andextracted with hexane, in a Sexhlet apparatus. The hexane was cooled andthe crystals collected and recrystallised to give the title compound(2.8 g.) m.p. 122°-5° C. (Found: C, 31.1; H, 3.1; N, 11.9. C₆ H₇ BrN₂ OSrequires C, 30.7; H, 3.0; N, 11.9%).

EXAMPLE 6 2-Bromo-4-(cyclopropylcarboxamido)thiazole

4-Amino-2-bromothiazole hydrobromide (15.6 g.) and cyclopropylcarbonylchloride (8.2 g.) were suspended in methylene chloride (100 ml.) withstirring and treated with pyridine (16 ml.) maintaining reactiontemperature at 0° C. with an ice bath. After completing the addition,the reaction mixture was stirred at room temperature for 3 hours, thenpoured onto 20% aqueous sodium acetate and stirred for 30 minutes. Themixture was separated and the organic layer washed with 2N hydrochloricacid, water, sodium carbonate solution and water. The organic layer wasdried and the solvent removed in vacuo and the residue recrystallisedthree times from carbon tetrachloride to give the title compound (7.3 g)m.p. 152°-3° C. (Found: C, 34.7; H, 3.0; N, 11.4. C₇ H₇ BrN₂ OS requiresC, 34.0; H, 2.9; N, 11.3%).

EXAMPLE 7 4-Diacetylamino-2-bromothiazole

A solution of 4-acetylamino-2-bromothiazole 10g, prepared as describedin Example 1, in acetic anhydride (100 ml) and pyridine (35 ml) wasstirred at 100° C. for 24 hours. The reaction mixture was cooled and theexcess acetic anhydride and pyridine removed in vacuo, and the residuewas re-evaporated three times with toluene. The residue was purified bycolumn chromatography using silica gel and eluting with chloroform, andrecrystallised from hexane to give the title compound (1.2 g) m.p.63°-65° C. (Found: C, 32.1; H, 2.8; H, 10.6 C₇ H₇ BrN₂ O₂ S requires C,32.0; H, 2.7; N, 10.7%)

EXAMPLE 8 2-Bromo-4-(n-butyramido)thiazole

4-Amino-2-bromothiazole hydrobromide (15.6g) and n-butyryl chloride(8.3g) were suspended in methylene chloride (100 ml) with stirring andtreated with pyridine (16ml.) over 15 minutes; maintaining reactiontemperatures at 0° C. with an ice bath. After the addition was complete,the reaction mixture was stirred at room temperature for 3 hours, thenpoured onto 20% aqueous sodium acetate (500 ml) and stirred for 30minutes. The mixture was separated and the organic layer washed with 2Nhydrochloric acid, water, sodium carbonate solution and water. Theorganic layer was dried (MgSO₄) and the solvent removed in vacuo and theresidue recrystallised twice from carbon tetrachloride and once frommethanol to give the title compound (3g). m.p. 119°-20° C. (Found: C,34.3; H, 3.7; N, 11.2. C₇ H₉ BrN₂ OS requires C, 33.8; H, 3.6; N,11.3%).

EXAMPLE 9 4-Acrylamido-2-bromothiazole

4-Amino-2-bromothiazole hydrobromide (15.6g) and acryloylchloride (7g)were suspended in methylene chloride (100 ml) with stirring and treatedwith pyridine (16 ml.), maintaining reaction temperature at 0° C. withan ice bath. After addition was complete, the reaction mixture wasstirred at room temperature for 3 hours, then poured onto 20% aqueoussodium acetate and stirred for 30 minutes. The mixture was filtered andseparated and the organic layer washed with 2N hydrochloric acid, water,sodium carbonate solution and water. The organic layer was dried (MgSO₄)and the solvent removed in vacuo. The residue was recrystallised fromcarbon tetrachloride to give the title compound (0.7 g) m.p. 152°-4° C.(Found: C, 30.5; H, 2.2; N, 11.8. C₆ H₅ BrN₂ OS requires C, 30.9; H,2.2; N, 12.0%).

EXAMPLE 10 2-Bromo-4-trichloroacetamidothiazole

4-Amino-2-bromo-thiazole hydrobromide (15.6g) and trichloroacetylchloride (14.3 g) were suspended in methylene chloride (100 ml) withstirring and treated dropwise with pyridine (16 ml) over 15 minutesmaintaining reaction temperatures at 0° C. with an ice bath. Aftercompleting the addition, the reaction mixture was stirred at roomtemperature for 3 hours, then poured onto 20% aqueous sodium acetate(250 ml.) and stirred for 30 minutes. The mixture was separated and theorganic layer washed with 2N hydrochloric acid, water, sodium carbonatesolution and water. The organic layer was dried (MgSO₄) and the solventremoved in vacuo and the residue treated with charcoal in hexane andrecrystallised from hexane to give the title compound (10.5g) m.p.77°-80° C. (Found: C, 19.0; H, 0.7 N, 8.5. C₅ H₂ Cl₃ BrN₂ OS requires C,18.5; H, 0.6; N, 8.6%)

EXAMPLE 11 4-Acetamido-2-chlorothiazole

A solution of 2-chlorothiazole-4-carbonylazide (1) (2g) in a mixture ofacetic anhydride (12 ml) and acetic acid (4 ml) was heated on a steambath for 1 hour then cooled and filtered. The precipitate was purifiedto give the bis-thiazolylurea (2).

The filtrate was evaporated under reduced pressure and the residue wasdissolved in ethanol and re-evaporated. The residue was sublimed twiceunder reduced pressure (14mm, 120° C.) to give the title compound(500mg, 20%) m.p. 153° C. (Found: C, 33.9; H, 2.85; N, 15.8%. C₅ H₅ ClN₂OS requires: C, 34.0; H, 2.85; N, 15.9%).

(1) A suspension of 2-chlorothiazole-4-carbohydrazine prepared asdescribed in Helv. Chim. Acta 29 1946) 1229 (4.5g, 25mM) in water (35ml) was treated with hydrochloric acid (9ml), cooled to 0° C. thentreated dropwise with a solution of sodium nitrite (2.25g) in water(7.5ml). Strong cooling was required to maintain the internaltemperature in the range 0° to 5° C. After 15 minutes the product wasremoved by filtration, washed with cold water (10 ml) and air dried.Recrystallisation from hexane (with charcoal treatment) gave2-chlorothiazole-4-carbonylazide (2g, 42%) mp >250° (d).

(2) The azide (2g) was dissolved in a mixture of acetic anhydride (12ml) and acetic acid (4 ml) and the mixture heated on a steam bath for 1hour. After cooling, the product was removed by filtration andrecrystallised from ethanol to give N,N'-bis-2-chloro-4-thiazolylureacompound (0.5g, 15%) mp: 250° C. (d). (Found: C, 28.8; H, 1.6; N, 18.8%C₇ H₄ Cl₂ N₄ OS₂ requires: C, 28.5; H, 1.4; N, 19.0%)

From the acetic anhydride/acetic acid mother liquors4-Acetamido-2-chlorothiazole was isolated as described above.

EXAMPLE 12 2-Chloro-4-formamidothiazole (a)2-Chlorothiazole-4-carbonylazide

A suspension of 2-chlorothiazole-4-carbohydrazine prepared as describedin Helv.Chim.Acta 29 (1946) 1229 (4.5g, 25mM) in water (35 ml) wastreated with hydrochloric acid (9 ml.), cooled to 0° C. then treateddropwise with a solution of sodium nitrite (2.25g) in water (7.5 ml.).Strong cooling was required to maintain the internal temperature in therange 0° to 5° C. After 15 minutes the product was removed byfiltration, washed with cold water (10 ml) and air dried.Recrystallisation from hexane (with charcoal treatment) gave2-chlorothiazole-4-carbonylazide (2g, 42%) mp >250° (d).

(b) 2-Chloro-4-formamidothiazole

99% Formic acid (50 ml) was added slowly to acetic anhydride (100 ml.)with cooling, then the mixture was heated at 50° C. for 15 minutes. Themixture was cooled to 0° C. to give a solution of formic-aceticanhydride in acetic acid.

2-Chlorothiazole-4-carboxylazide (2g) was dissolved in the formic-aceticanhydride solution (20 ml) and the solution was heated for 1 hour on asteam bath. The solvents were removed under reduced pressure and theresidue evaporated twice with ethanol. The residue was sublimed twiceunder reduced pressure (14 mm/120° C.) to give the title compound(800mg, 50%) m.p. 138° C. (Found: C, 29.7; H, 1.95; H, 17.1% C₄ H₃ ClN₂OS requires: C, 29.6; H, 1.8; N, 17.2%).

EXAMPLE 13 2-Bromo-4-formamidothiazole

Acetic anhydride (100 ml.) was cooled to 0° C. and treated with 98%formic acid (50 ml.). The resulting mixture was heated at 50° C. for 15minutes then cooled to 0° C. To this solution of formic-acetic anhydridewas added 4-amino-2-bromothiazole hydrobromide (26 g, 0.1 m) followeddropwise by pyridine (25 ml.). The reaction mixture was allowed to standfor 1 hour at room temperature then poured onto 20% aqueous sodiumacetate solution (500 ml.). The resulting cyrstals were removed byfiltration, washed once with water (100 ml.) then recrystallised fromethanol to give the 2-bromo-4-formamidothiazole (12 g, 58%). m.p. 167°C. d. (Found: C, 23.55; H, 1.6; N, 13.45. C₄ H₃ N₂ BrOS requires C,23.2; H, 1.45; N, 13.5%).

EXAMPLE 14 2-Bromo-4-formamido-5-methylthiazole

4-Amino-2-bromo-5-methylthiazole is treated with formic-acetic anhydride(prepared as described in Example 12b) to give the title compound.

EXAMPLE 15 4-(N-acetyl-N-formyl)amino-2-bromothiazole

4-Acetamido-2-bromothiazole (prepared as described in Example 1) istreated with formic-acetic anhydride to give the title compound.

EXAMPLE 16 4-(N-Acetyl-N-formyl)amino-2-bromothiazole

A solution of 2-bromo-4-formamidothiazole (2.07g, 10mM) and acetylchloride (8 ml) in ethylene dichloride (200 ml.) was stirred at 60° C.for 24 hours in the presence of powdered 4A molecular sieve (45g). Thereaction mixture was cooled to ambient temperature and filtered. Thefiltrate was evaporated under reduced pressure and then residuetriturated with toluene (20 ml.). The solution was filtered, thefiltrate evaporated and the residue recrystallised from diethyl ether at-78° to give the title compound (600 mg, 24%) m.p. 62°. (Found: C, 29.3;H, 2.1; N, 11.3%. C₆ H₅ N₂ BrO₂ S requires C, 28.9; H, 2.0; N, 11.1%).

EXAMPLE 17 2-Bromo-4-(N-methylacetamido)thiazole

A solution of 4-acetamido-2-bromothiazole (prepared as described inExample 1) and methyl tosylate (4.65g, 25mM) in dry acetonitrile (125ml.) was treated with a 60% dispersion of sodium hydride in oil (1g,25mM) and the mixture stirred 72 hours at ambient temperature. Thereaction mixture was filtered and the filtrate evaporated under reducedpressure. The residue was chromatographed on silica (Woelm grade 1,150g) using 2% methanol in chloroform as eluant. Evaporation of theappropriate fractions followed by recrystallisation from hexane gave thetitle compound (1.9g, 32%) mp 84° C. Found: C, 30.55; H, 2.95; N, 11.8%.C₆ H₇ N₂ BrOS requires C, 30.7; H, 3.0; N,.11.9%).

The invention includes a compound of formula I ##STR11## where Hal ischlorine or bromine, R¹ is hydrogen or methyl and R is ethenyl orcyclopropyl.

Preferred compounds of formula I are 4-acrylamido2-bromothiazole and2-bromo-4-(cyclopropylcarboxamido)thiazole.

The above compounds of formula I may be prepared by methods given above.

I claim:
 1. A compound of formula I ##STR12## where Hal is chlorine orbromine, R¹ is hydrogen or methyl and R is ethenyl or cyclopropyl.
 2. Acompound as claimed in claim 1 which is 4-acrylamido-2-bromothiazole. 3.A compound as claimed in claim 1 which is2-bromo-4-(cyclopropylcarboxamido)thiazole.